Over the centuries, large numbers of polymorphisms in drug receptors, drug effector pathways, and other proteins developed. Some variant alleles have prospered in the absence of exposures to modern medications. With the epidemic of exposure to pharmacologically-active licit drugs of many classes, gene-drug interactions are likely to be a fruitful area of research in the application of molecular biology to public health. The focus of this revised competing-continuation application is hypertension. Pilot data were used to select drug-gene interactions for study. The primary aims are to assess drug-gene interactions on the incidence of myocardial infarction and stroke for (1) the alpha adducin polymorphism and diuretic use; (2) the beta-2 adrenergic receptor-27 (B2AR27) polymorphism and beta-blockers; and (3) the ACE insertion/deletion polymorphism and the ACE inhibitor use. Secondary aims include other potential gene-drug interactions with the G-protein beta-3 subunit (GB3) polymorphism, B2AR-16 polymorphism, the amiloride-sensitive epithelial sodium channel, and the angiotensinogen Met235Thr polymorphism. A tertiary aim is to use DNA extracted from surgical or pathological specimens to assess genotypes in fatal cases. This project is responsive to PA-99-016 since one aim is to identify genes that cause variation in drug response. The setting is Group Health Cooperative (GHC). GHC computerized files will be used to identify all treated hypertensive patients, aged 30 to 79 years, with incident MI or stroke during 1/1995 - 1/2004. Population-based controls with treated hypertension will be sampled from the GHC enrollment files. Data collection will include review of the ambulatory medical record, telephone interviews of consenting cases and controls, and the collection of venous blood specimen. Standard methods will be used to extract DNA and assay variant alleles. The GHC computerized pharmacy records will serve as the primary source of information about the use of antihypertensive medication. Frequency matching will control for the potential confounding effects of age, gender and year of presentation, and data analysis will involve restriction, stratification, and logistic regression. Case-control and case-only analyses are planned. Collecting data for an additional 5 years will identify 380 stroke cases, 760 MI cases and an additional 2,280 controls. For the alpha-adducin-diuretic interaction, for instance, this study will have 88 percent power to detect a multiplicative synergy index of 0.58 (the difference between an odds ratio of 0.46 and 0.79 in subjects with and without the variant, respectively). Power for other primary aims is excellent; power for secondary aims is good to excellent.